Drug-resistance in cancer is the major impediment to a successful treatment and the most difficult problem that needs to be overcome in order to ensure successful treatment of cancer. Multidrug-resistance (MDR) in cancer cells is generally a phenotype whereby cells display a reduced sensitivity to chemotherapeutic compounds based on several mechanisms, in particular due to an increase in drug efflux as most relevant form of MDR (Han, L. et al., Nat Prod Res, 2015, 1-4). Said multidrug-resistance can be a pre-existing one and, thus, evident at the onset of therapy (intrinsic) or alternatively be acquired after onset of therapy.
Members of the family of membrane proteins named ATP binding cassette (ABC transporter proteins) transporters or pumps usually consist of four domains which include two trans-membrane domains (TMDs) and two nucleotide binding domains (NBDs) as minimum functional unit to transport a substrate such as a chemotherapeutic compound triggered by ATP binding and respective hydrolysis. Members of said family are notorious mediators of MDR, actively effluxing a wide range of therapeutic compounds such as chemotherapeutic compounds irrespective of their concentration gradient. This significantly lowers their intracellular concentrations and, thus, their therapeutic effects in those cells. A prominent ABC transporter protein subfamily reported to modulate anticancer drug uptake is the “B” subfamily in particular with P-glycoprotein (P-gp, MDR1, or ABCB1) or ABCB5 including respective isoforms. Besides, common ABC transporters include the “C” subfamily such as with multidrug-resistance protein (MRP1 or ABCC1) and the “G”-subfamily such as with breast cancer resistance protein (ABCG2 or MXR).
ABC transporter proteins have been found to be constitutively expressed and overexpressed, respectively, in many multidrug-resistant cancers, wherein P-glycoprotein is considered for being a key player in the multidrug-resistant phenotype in cancer. Thereby, the expression of P-glycoprotein in multidrug-resistant cancer cells seems to be regulated by a wide range of factors including hypoxia, metabolic acidosis, generation of reactive oxygen species, namely P-glycoprotein is considered for being an important responder to chemical insult or environmental influences on cancer (Callaghan, R. et al., Drug Metab Dispos 2014, 42:623-31).
For example, expression and overexpression, respectively, of P-glycoprotein has been found in various types of cancers with resistance against commonly used and standard chemotherapeutic compounds such as anthracyclines, vinca alkaloids, topoisomerase-I and -II inhibitors, taxanes and the like, for example against doxorubicin or paclitaxel (taxol). Its broad specificity has been the subject of major attempts to inhibit said protein pump activity and to sensitize the potency of chemotherapeutic compounds (Callaghan, R. et al., Drug Metab Dispos 2014, 42:623-31). Accordingly, a strategy is to identify small-molecules that either act as direct P-glycoprotein inhibitors or compete with chemotherapeutic compounds for transport. Furthermore, the resolved structure of P-glycoprotein further revealed a molecular basis for poly-specific drug binding crucial for the lead optimization of chemotherapeutic compounds and MDR modulators (Aller, S. G. et al., Science, 2009, 323:1718-22).
MDR modulators developed so far, however, fail to provide sufficient inhibition of ABC transporter proteins such as P-glycoprotein and/or did not demonstrate sufficient clinical utility in overcoming multidrug-resistance. Besides, most of the ABC transport protein inhibitors described so far have been initially developed for the treatment of other diseases than cancer like verapamil and these main drug activities may, thus, appear as non-tolerable side effects in cancer therapy. Unfortunately, progress in this area has been rather slow although having effective treatment options for multidrug-resistant cancer gets more and more important today.
Consequently, there is a strong need for methods and means allowing for an effective therapeutic treatment especially of multidrug-resistant cancer and cancer cells with a multidrug-resistant phenotype, respectively. In particular, efficacious treatment options are urgently required for specifically treating subjects with multidrug-resistant cancer with expression or overexpression of ABC transporter proteins, especially of P-glycoprotein, i.e. for treating said specific subgroup of subjects amongst subjects with cancer.